The invention relates to compounds and their uses, particularly in the pharmaceutical industry. The invention discloses compounds having anti-proliferative activities, as well as methods for treating various diseases associated with abnormal cell proliferation, including cancer, by administering said compounds. It further deals with pharmaceutical compositions comprising said compounds, more particularly useful to treat cancers.
Cancer is still one of the leading causes of death in developed countries, as cancer affects all ages, sexes, racial and ethnic groups. According to the American Association for Cancer Research, one out of five deaths in the US is caused by cancer. Worldwide, the most predominant cancer sites are lung (14%), prostate (13%), breast (11%) and colorectal (11%) (data obtained from the Cancer Statistic Branch, NCI).
Cancer rate is increasing in developed countries in spite of falling incidence of several cancers such as prostate cancer (due to detection programs) or lung cancer in men (due to prevention programs). Among the fastest increasing cancer rates are non-Hodgkin""s lymphoma cancer and melanoma (3% annual rise) in the US (The Annual Report to the Nation on the Status of Cancer, 1973-1997).
Unlike cancer incidence, cancer deaths have declined in developed countries. This is due in part to better therapy designs but also to prevention programs and better detection of some cancers at an earlier stage.
However, in spite of higher achievements in treatment and prevention of cancers, several improvements are awaited for:
effective therapies for early stage cancer to reduce relapses,
alternative therapies for curing tumors refractory to standards therapies,
alternative therapies for curing metastatic cancers
less toxic drugs, and
better delivery systems.
Inhibitors of cell signaling pathways could represent such a new alternative therapy by addressing the first three issues, when used alone or in combination with standard chemotoxic drugs.
There are various receptors, enzymes and effector molecules involved in the biochemical pathways necessary for signal processing in a cell. These include small GTPases, which are monomeric guanine nucleotide-binding proteins of 20-25 kDa molecular mass, which function as molecular switches. They are xe2x80x9conxe2x80x9d in the GTP-bound state and xe2x80x9coffxe2x80x9d in the GDP-bound state. Cycling between the active and inactive forms is controlled by several accessory proteins: the guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and GDP dissociation inhibitors (GDIs). The active GTP-bound GTPases interact with a variety of effectors proteins to produce their cellular effects.
Ras, the first GTPase discovered, gave rise to the Ras super family of GTPases. It is a key regulator of cell growth and is found in mutated oncogenic forms in a large number of human tumors. When specific residues in Ras are mutated, this protein becomes constitutively active (insensitive to GAP action) and causes cell transformation. The Ras oncoproteins are among the most potent mitogenic polypeptides known, and activating mutations of Ras are found in nearly one-third of all human cancers.
The Rho subfamily of GTPases is composed of 3 major subtypes, namely Rho, Rac, and Cdc42, which control actin cytoskeleton in distinct ways. Other major roles for the Rho proteins are the regulation of gene transcription (JNK and p38 mitogen-activated protein kinase, serum response factor, NFkB), cell cycle progression, and adhesion. Several Rho GTPases have been shown to play an important role in cell transformation.
U.S. Pat. No. 4,590,201 discloses compound L651582, a cell signaling inhibitor. This compound inhibits proliferation and inflammation by affecting the biochemical pathways necessary for signal processing in the cell. It is an indirect blocker of the effector enzymes which produce the second messengers necessary to induce growth.
The present invention now relates to the identification and characterization of a new class of compounds which present an anti-cell proliferation effect, more particularly on tumor cells. Without being bound by any theory, this effect is believed to be due to an activity on cell signaling, as described above. In particular, as illustrated in the examples, the compounds of this invention inhibit the oncogenic properties of the above family of proteins, potentially by impairing the nucleotide exchange. Advantageously, these compounds will inhibit or reverse malignant cell phenotypes in a wide array of human tissues, have little or no effect on normal cell physiology, will be highly active so that a limited number of treatments will be needed for each patient, and will have excellent bio availability and pharmacokinetic properties.
Accordingly, one aspect of the invention is to provide a compound having a general formula (I): 
wherein:
R1 is CH2R3 or COR3;
R2 represents a hydrogen atom or an alkenyl group containing from 3 to 6 carbon atoms;
R3 is xe2x80x94OH, xe2x80x94OR4, xe2x80x94SR4, xe2x80x94NR5R6, or 
R4 represents a group selected from alkyl containing from 1 to 6 carbon atoms, aryl, aralkyl, alkanoyl from 2 to 6 carbon atoms and arylcarbonyl;
R5 and R6, independently from each other, are selected from a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl;
m is 2 or 3;
n represents an integer between 1 and 10 inclusive;
X represents an oxygen atom, a sulfur atom or a radical xe2x80x94NR7xe2x80x94;
Y represents an oxygen atom, a sulfur atom or a radical xe2x80x94NR7xe2x80x94;
R7, identical or different, is selected in a group consisting of a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl;
A represents either a substituted phenyl group of formula 
xe2x80x83in which:
R8, R9, R10 and R11, independently from each other, are selected from a hydrogen atom, a halogen atom (preferably F, Cl, or Br), a hydroxyl group, a (C1-C10)alkyl group, an (C1-C10)alkanoyl group, a (C1-C10)alkoxy group, an aryl group, an aralkyl group, an arylcarbonyl group, a mono- or poly-cyclic hydrocarbon group, xe2x80x94NO2, xe2x80x94CN, a xe2x80x94NR12R13 group or a trifluoro(C1-C6)alkyl group; R8, R9, R10 and R11, not being simultaneously hydrogen atom,
or alternatively two substituents, R8 and R9, may form together a mono- or poly-cyclic hydrocarbon group with the carbon atoms of the phenyl group they are attached and the two other substituents, R10 and R11, are as defined above;
or A represents a 5- or 6-membered heterocyclic ring which has 1 to 3 hetero-atoms selected from oxygen, sulfur and nitrogen, said ring is bonded directly to X;
R12 and R13, independently from each other, are selected in the group consisting of a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl;
with the provisos that:
when X and Y are oxygen atoms, R2 is a hydrogen atom, n is 5 and R8 on the ortho position on the phenyl group vis-à-vis X is n-propyl group, then R9, R10 and R11 are different from hydrogen;
when X and Y are oxygen atoms, R2 is a hydrogen atom, n is 5, R8 on the ortho position on the phenyl group vis-à-vis X is n-propyl group, R9 on the meta position vis-à-vis X is an hydroxyl group, and R10 on the para position vis-à-vis X is an acetyl group; then R11 is different from hydrogen;
when X and Y are oxygen atoms, R2 is a hydrogen atom, n is 2 or 3, then A is different from a non-substituted naphthalene group;
its tautomers, optical and geometrical isomers, racemates, salts, hydrates and mixtures thereof.
The compounds of the present invention may have one or more asymmetric centers and it is intended that stereoisomers (optical isomers), as separated, pure or partially purified stereoiomers or racemic mixtures thereof are included in the scope of the invention.
The present invention also relates to pharmaceutical compositions comprising at least one compound as defined above in a pharmaceutically acceptable support, optionally in association with another active agent.
The present invention also relates to the use of a compound as defined above, for the manufacture of a medicament for the treatment of diseases associated with abnormal cell proliferation, such as cancers.
The present invention also includes methods of treating diseases associated with abnormal cell proliferation, such as cancers, comprising the administration to a subject in need thereof of an effective amount of a compound as defined above.
As will be further disclosed in this application, the compounds according to this invention have strong cell proliferation inhibitory activity and are effective at reducing or arresting growth of proliferating cells such as tumor cells.
Within the context of the present application, the terms alkyl and alkoxy denote linear or branched saturated groups containing from 1 to 6 carbon atoms. An alkoxy group denotes an xe2x80x94O-alkyl group.
The alkyl groups may be linear or branched. Examples of alkyl groups having from 1 to 10 carbon atoms inclusive are methyl, ethyl, propyl, isopropyl, t-butyl, n-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 2-ethylhexyl, 2-methylbutyl, 2-methylpentyl, 1-methylhexyl, 3-methylheptyl and the other isomeric forms thereof. Preferably, the alkyl groups have from 1 to 6 carbon atoms.
The alkenyl groups may be linear or branched. Examples of alkenyl containing from 3 to 6 carbon atoms are 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the isomeric forms thereof.
The term aryl includes any aromatic group comprising preferably from 5 to 14 carbon atoms, preferably from 6 to 14 carbon atoms, optionally interrupted by one or several heteroatoms selected from N, O, S or P. Most preferred aryl groups are mono- or bi-cyclic and comprises from 6 to 14 carbon atoms, such as phenyl, xcex1-naphtyl, xcex2-naphtyl, antracenyl, or fluorenyl group.
The term aralkyl group generally stands for an aryl group attached to an alkyl group as defined above, such as benzyl or phenethyl.
The term mono- or poly-cyclic hydrocarbon group is understood to refer to hydrocarbon cyclic group having from 1 to 20 carbon atoms, optionally interrupted with one or more heteroatoms selected in the group N, O, S and P. Among such mono- or poly-cyclic hydrocarbon groups, cyclopentyl, cyclohexyl, cycloheptyl, 1- or 2-adamantyl groups, pyran, piperidine, pyrrolidine, morpholine, dioxan, tetrahydrothiophene, and tetrahydrofuran can be cited. The mono- or poly-cyclic hydrocarbon group may form with the phenyl group it is attached an aryl group, such as a xcex1-naphtyl, xcex2-naphtyl, or antracenyl group.
An alkanoyl group is a xe2x80x94CO-alkyl group, the alkyl group being as defined above.
The term arylcarbonyl group generally stands for an aryl group attached to a carbonyl group, the aryl group being as defined above.
The term 5- or 6-membered heterocyclic ring includes pyrrole, pyridine, furan, thiophene, pyrimidine, pyrazine, imidazole, thiazole, oxazole, indole, purine, benzo[b]furan, benzo[b]thiophene, isoquinoline, quinoline, 6,7-dihydro-5H-(2)pyridine, 1H-pyrazolo[3,4-b]pyridine, thienopyridine.
The alkyl, alkenyl, aryl, aralkyl, mono- or poly-cyclic hydrocarbon group, and the 5- or 6-membered heterocyclic ring may be optionally substituted with one or more groups selected from hydroxyl group, halogen atom, cyano group, nitro group, ester (xe2x80x94COO(C1-C6)alkyl group), xe2x80x94OCO(C1-C6)alkyl group, amide (xe2x80x94NHCO(C1-C6)alkyl or xe2x80x94CONH(C1-C6)alkyl group), (C1-C10)alkyl radical, (C1-C10)alkoxy radical, mono- or poly-cyclic hydrocarbon group, Cxe2x95x90O group, a xe2x80x94NR12R13 group or a trifluoro(C1-C6)alkyl group.
Preferably, R12 and R13 are hydrogen atom or ethyl group.
The trifluoro(C1-C6)alkyl group is preferably the trifluoromethyl group.
In a particular embodiment, when R3 represents xe2x80x94NR5R6, preferably R5 is a hydrogen atom and R6 is selected from an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl.
According to preferred embodiments, the compounds according to the invention correspond to general formula (I) wherein:
X is oxygen; and/or
Y is oxygen; and/or
n is from 4 to 7 inclusive; and/or
R1 is xe2x80x94CH2OH, xe2x80x94CH2xe2x80x94O-benzyl, xe2x80x94CO2H or xe2x80x94COxe2x80x94NH-benzyl; and/or
R2 is a hydrogen atom or a propen-1-yl group; and/or
A is a substituted phenyl as defined above.
In a preferred embodiment, when A is a substituted phenyl, the substituted phenyl presents the following formula: 
In a particular embodiment, when A is a substituted phenyl as defined above, at least one of the substituents on the phenyl group is an halogen atom, more preferably chlorine.
A particular preferred group of compounds according to the present invention, are the compounds of formula (I) wherein at least two substituents simultaneously represent Cl.
Another particular preferred group of compounds according to the present invention, are the compounds of formula (I) wherein R8 represents a hydrogen atom, a propyl group or an ethoxy group, R9 and R10 represent a hydrogen atom, or an halogen atom, preferably chlorine, and R11 is a hydrogen atom.
When the compounds according to the invention are in the forms of salts, they are preferably pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula I with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol, etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, fonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. Mixture of solvents may also be used.
Specific examples of compounds of formula (I) which fall within the scope of the present invention include the following compounds:
5-[5-(4-Chlorophenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(3-Chlorophenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(3,4-Dichlorophenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[4-(3,4-Dichlorophenyloxy)butyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(3,4-Dichloro-2-propylphenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(4,5-Dichloro-2-propylphenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(2-Ethyloxyphenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[6-(3,4-Dichloro-2-propylphenyloxy)hexyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[7-(3,4-Dichloro-2-propylphenyloxy)heptyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[9-(3,4-Dichlorophenyloxy)nonyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
2-(Benzyloxymethyl)-5-[5-(3,4-dichlorophenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(4-Chlorophenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[5-(3-Chlorophenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[5-(3,4-Dichlorophenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[4-(3,4-Dichlorophenyloxy)butyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[5-(3,4-Dichloro-2-propylphenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[5-(2-Ethyloxyphenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
N-Benzyl-5-[5-(4-chlorophenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxamide
(E)-3-[5-(4-Chlorophenyloxy)pentyloxy]-6-(hydroxymethyl)-2-(propen-1-yl)-4H-pyran-4-one
(E)-3-[5-(3-Chlorophenyloxy)pentyloxy]-6-(hydroxymethyl)-2-(propen-1-yl)-4H-pyran-4-one
(E)-3-[5-(3,4-Chlorophenyloxy)pentyloxy]-6-(hydroxymethyl)-2-(propen-1-yl)-4H-pyran-4-one
(E)-3-[5-(3,4-Chloro-2-propylphenyloxy)pentyloxy]-6-(hydroxymethyl)-2-(propen-1-yl)-4H-pyran-4-one
(E)-6-(Hydroxymethyl)-2-(propen-1-yl)-3-[5-(2-propylphenyloxy)pentyloxy]-4H-pyran-4-one
(E)-3-[5-(4-Chlorophenyloxy)pentyloxy]-2-(propen-1-yl)-4-oxo-4H-pyran-6-carboxylic acid
(E)-3-[5-(3-Chlorophenyloxy)pentyloxy]-2-(propen-1-yl)-4-oxo-4H-pyran-6-carboxylic acid
(E)-3-[5-(3,4-Dichlorophenyloxy)pentyloxy]-2-(propen-1-yl)-4-oxo-4H-pyran-6-carboxylic acid
(E)-3-[5-(3,4-Dichloro-2-propylphenyloxy)pentyloxy]-2-(propen-1-yl)-4-oxo-4H-pyran-6-carboxylic acid
(E)-2-(Propen-1-yl)-3-[5-(2-propylphenyloxy)pentyloxy]-4-oxo-4H-pyran-6-carboxylic acid.
A particularly preferred compound is 5-[5-(3,4-dichloro-2-propylphenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one.
The compounds according to the present invention may be prepared by various methods known to those skilled in the art. More preferably, two chemical routes have been carried out. The first one (Scheme 1) includes an alkylation of kojic acid with the corresponding alkylbromide, which gives rise to the desired 2-(hydroxymethyl)-4H-pyran-4-ones 1. These compounds may be then oxidized, typically with chromium trioxide in sulfuric acid, to produce the acid derivatives 2, which can be readily converted into the corresponding analogues of general structure 3. Additionally, the hydroxymethyl derivatives 1 provide the compounds 4 by standard procedures. 
Step a) of this method is more preferably conducted in a solvent, such as DMF, at a temperature comprised between 40 and 70xc2x0 C., typically around 50xc2x0 C.
In step b), the compounds are preferably reacted in the presence of the Jones reagent and in a solvent, such as acetone, while the temperature is decreased to reach room temperature.
The second preferred chemical route (Scheme 2) corresponds to an alkylation of kojic acid with allylbromide, which gives rise the 4H-pyran-4-one derivative 5. This compound is then thermally isomerised to 6. The general protocol for the O-alkylation produces simultaneously not only the alkylation but also the migration of the double bond to the conjugated position affording derivatives 7. These alcohols are oxidized with Jones reagent to provide the acids of general structure 8. Compounds 7 and 8 are derived to give analogues 9 and 10. 
For both described series, yields are generally comprised between 55 and 75% by weight. These methods for preparing compounds of formula (I) represent further objects of the present application.
It should be understood that other ways of producing these compounds may be designed by the skilled person, based on common general knowledge and following guidance contained in this application.
In order to prepare compounds of formula (I) wherein Y is NR7, kojic acid can be first protected on the hydroxyl group and then be reacted with R7NH2 to give rise a N-pyridone derivative (J. Heterocyclic Chemistry, 1986, 23 : 5-8). This N-pyridone derivative is thereafter deprotected and may react as described above following schemes 1 and 2. Another synthesis of N-substituted-pyridone is described by Korenova, A et al. in J. Chem. Pap, 1997, No.6, 51, 383-389.
As indicated above, a further object of this invention relates to a pharmaceutical composition comprising at least one compound of formula (I), as defined above, and a pharmaceutically acceptable vehicle or support.
The compounds may be formulated in various forms, including solid and liquid forms, such as tablets, gel, syrup, powder, aerosol, etc.
The compositions of this invention may contain physiologically acceptable diluents, fillers, lubricants, excipients, solvents, binders, stabilizers, and the like. Diluents that may be used in the compositions include but are not limited to dicalcium phosphate, calcium sulphate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and for prolonged release tablet-hydroxy propyl methyl cellulose (HPMC). The binders that may be used in the compositions include but are not limited to starch, gelatin and fillers such as sucrose, glucose, dextrose and lactose.
Natural and synthetic gums that may be used in the compositions include but are not limited to sodium alginate, ghatti gum, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone and veegum. Excipients that may be used in the compositions include but are not limited to microcrystalline cellulose, calcium sulfate, dicalcium phosphate, starch, magnesium stearate, lactose, and sucrose. Stabilizers that may be used include but are not limited to polysaccharides such as acacia, agar, alginic acid, guar gum and tragacanth, amphotsics such as gelatin and synthetic and semi-synthetic polymers such as carbomer resins, cellulose ethers and carboxymethyl chitin.
Solvents that may be used include but are not limited to Ringers solution, water, distilled water, dimethyl sulfoxide to 50% in water, propylene glycol (neat or in water), phosphate buffered saline, balanced salt solution, glycol and other conventional fluids.
The dosages and dosage regimen in which the compounds of formula (I) are administered will vary according to the dosage form, mode of administration, the condition being treated and particulars of the patient being treated. Accordingly, optimal therapeutic concentrations will be best determined at the time and place through routine experimentation.
The compounds according to the invention can also be used enterally. Orally, the compounds according to the invention are suitable administered at the rate of 100 xcexcg to 100 mg per day per kg of body weight. The required dose can be administered in one or more portions. For oral administration, suitable forms are, for example, tablets, gel, aerosols, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules; a preferred method of administration consists in using a suitable form containing from 1 mg to about 500 mg of active substance.
The compounds according to the invention can also be administered parenterally in the form of solutions or suspensions for intravenous or intramuscular perfusions or injections. In that case, the compounds according to the invention are generally administered at the rate of about 10 xcexcg to 10 mg per day per kg of body weight; a preferred method of administration consists of using solutions or suspensions containing approximately from 0.01 mg to 1 mg of active substance per ml.
The compounds of formula (I) can be used in a substantially similar manner to other known anti-tumor agents for treating (both chemopreventively and therapeutically) various tumors. For the compounds of this invention, the anti-tumor dose to be administered, whether a single dose, multiple dose, or a daily dose, will of course vary with the particular compound employed because of the varying potency of the compound, the chosen route of administration, the size of the recipient, the type of tumor, and the nature of the patient""s condition. The dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects. An oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, appropriate protocols for the effective administration of the compounds of this present invention, such as by referring to the earlier published studies on compounds found to have anti-tumor properties.
According to another aspect, the present invention relates to a method for the treatment of a disease associated with abnormal cell proliferation, comprising administering to a patient in need of such treatment an effective amount of at least one compound of general formula (I) as described above, wherein, in said formula (I):
R1 is CH2R3 or COR3;
R2 represents a hydrogen atom or an alkenyl group containing from 3 to 6 carbon atoms;
R3 is xe2x80x94OH, xe2x80x94OR4, xe2x80x94SR4, xe2x80x94NR5R6, or 
R4 represents a group selected from alkyl containing from 1 to 6 carbon atoms, aryl, aralkyl, alkanoyl from 2 to 6 carbon atoms and arylcarbonyl;
R5 and R6, independently from each other, are selected from a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl;
m is 2 or 3;
n represents an integer between 1 and 10 inclusive;
X represents an oxygen atom, a sulfur atom or a radical xe2x80x94NR7xe2x80x94;
Y represents an oxygen atom, a sulfur atom or a radical xe2x80x94NR7xe2x80x94;
R7, identical or different, is selected in a group consisting of a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl;
A represents either a substituted phenyl group of formula 
xe2x80x83in which:
R8, R9, R10 and R11, independently from each other, are selected from a hydrogen atom, a halogen atom (preferably F, Cl, or Br), a hydroxyl group, a (C1-C10)alkyl group, an (C1-C10)alkanoyl group, a (C1-C10)alkoxy group, an aryl group, an aralkyl group, an arylcarbonyl group, a mono- or poly-cyclic hydrocarbon group, xe2x80x94NO2, xe2x80x94CN, a xe2x80x94NR12R13 group or a trifluoro(C1-C6)alkyl group; R8, R9, R10 and R11 not being simultaneously hydrogen atom,
or alternatively two substituents, R8 and R9, may form together a mono- or poly-cyclic hydrocarbon group with the carbon atoms of the phenyl group they are attached and the two other substituents, R10 and R11, are as defined above;
or A represents a 5- or 6-membered heterocyclic ring which has 1 to 3 hetero-atoms selected from oxygen, sulfur and nitrogen, said ring is bonded directly to X;
R12 and R13, independently from each other, are selected in the group consisting of a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms, an aryl and an aralkyl;
its tautomers, optical and geometrical isomers, racemates, salts, hydrates and mixtures thereof.
Preferred compounds for use according to the invention include any sub-group as defined above, and, as specific examples, the following compounds:
5-[5-(4-Chlorophenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(3-Chlorophenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(3,4-Dichlorophenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[4-(3,4-Dichlorophenyloxy)butyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(3,4-Dichloro-2-propylphenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(4,5-Dichloro-2-propylphenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(2-Ethyloxyphenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[6-(3,4-Dichloro-2-propylphenyloxy)hexyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[7-(3,4-Dichloro-2-propylphenyloxy)heptyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[9-(3,4-Dichlorophenyloxy)nonyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
2-(Benzyloxymethyl)-5-[5-(3,4-dichlorophenyloxy)pentyloxy]-2-(hydroxymethyl)-4H-pyran-4-one
5-[5-(4-Chlorophenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[5-(3-Chlorophenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[5-(3,4-Dichlorophenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[4-(3,4-Dichlorophenyloxy)butyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[5-(3,4-Dichloro-2-propylphenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
5-[5-(2-Ethyloxyphenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxylic acid
N-Benzyl-5-[5-(4-chlorophenyloxy)pentyloxy]-4-oxo-4H-pyran-2-carboxamide
(E)-3-[5-(4-Chlorophenyloxy)pentyloxy]-6-(hydroxymethyl)-2-(propen-1-yl)-4H-pyran-4-one
(E)-3-[5-(3-Chlorophenyloxy)pentyloxy]-6-(hydroxymethyl)-2-(propen-1-yl)-4H-pyran-4-one
(E)-3-[5-(3,4-Chlorophenyloxy)pentyloxy]-6-(hydroxymethyl)-2-(propen-1-yl)-4H-pyran-4-one
(E)-3-[5-(3,4-Chloro-2-propylphenyloxy)pentyloxy]-6-(hydroxymethyl)-2-(propen-1-yl)-4H-pyran-4-one
(E)-6-(Hydroxymethyl)-2-(propen-1-yl)-3-[5-(2-propylphenyloxy)pentyloxy]-4H-pyran-4-one
(E)-3-[5-(4-Chlorophenyloxy)pentyloxy]-2-(propen-1-yl)-4-oxo-H-pyran-6-carboxylic acid
(E)-3-[5-(3-Chlorophenyloxy)pentyloxy]-2-(propen-1-yl)-4-oxo-4H-pyran-6-carboxylic acid
(E)-3-[5-(3,4-Dichlorophenyloxy)pentyloxy]-2-(propen-1-yl)-4-oxo-4H-pyran-6-carboxylic acid
(E)-3-[5-(3,4-Dichloro-2-propylphenyloxy)pentyloxy]-2-(propen-1-yl)-4-oxo-4H-pyran-6-carboxylic acid
(E)-2-(Propen-1-yl)-3-[5-(2-propylphenyloxy)pentyloxy]-4-oxo-4H-pyran-6-carboxylic acid
A further object of this invention is the use of an effective amount of at least one compound of formula (I) as defined above for the preparation of pharmaceutical composition for the treatment of a disease associated with abnormal cell proliferation.
Because of their cell proliferation inhibitory activity, the compounds of this invention are suitable for treating a variety of diseases in a variety of conditions. In this regard, xe2x80x9ctreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d include both therapeutic and prophylactic treatments. Accordingly, the compounds may be used at very early stages of a disease, or before early onset, or after significant progression, including metastasis. The term xe2x80x9ctreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d designates in particular a reduction of the burden in a patient, such as a reduction in cell proliferation rate, a destruction of diseased proliferative cells, a reduction of tumor mass or tumor size, a delaying of tumor progression, as well as a complete tumor suppression.
Typical examples of diseases associated with abnormal cell proliferation include cancers and restenosis, for instance. The compounds of this invention are particularly suited for the treatment of cancers, such as solid tumors or lymphoid tumors. Specific examples include prostate cancer, ovarian cancer, pancreas cancer, lung cancer, breast cancer, liver cancer, head and neck cancer, colon cancer, bladder cancer, non-Hodgkin ""s lymphoma cancer and melanoma.
The compounds may be administered according to various routes, typically by injection, such as local or systemic injection(s). Intratumoral injections are preferred for treating existing cancers. However, other administration routes may be used as well, such as intramuscular, intravenous, intradermic, subcutaneous, etc. Furthermore, repeated injections may be performed, if needed, although it is believed that limited injections will be needed in view of the efficacy of the compounds.
A further object of this invention is a method for reducing cancer cell proliferation by administering in a subject having cancer an effective amount of compound of formula (I) as defined above.
A further object of this invention is a method for treating metastatic cancers by administering in a subject in need of such treatment an effective amount of compound of formula (I) as defined above.
A further object of this invention is the use of a compound as defined above for the preparation of a pharmaceutical composition for treating metastatic cancers or for reducing cancer cell proliferation.
Further aspects and advantages of this invention will be disclosed in the following examples, which should be regarded as illustrative and not limiting the scope of this application.